FEATURES OF CHOLESTEROL STRUCTURE THAT REGULATE THE CLEARANCE OF CHYLOMICRON-LIKE LIPID EMULSIONS

Cholesterol is an absolute requirement for the clearance from plasma o f the remnants of triglyceride-rich lipoproteins. Our laboratory previ ously established that cholesterol was essential for the hepatic uptak e of remnant particles after intravenous injection of chylomicron-like lipid emulsions (1). The aim of the present study was to determine th e structural features of the cholesterol molecule that regulate the me tabolism of chylomicrons. Chylomicron-like lipid emulsions, which refl ect the size and composition and mimic the physiology of lymph chylomi crons, were prepared with tracer amounts of labeled triolein ([C-14]TO ) and cholesteryl oleate ([H-3]CO) to follow the hydrolysis of triglyc eride and the uptake of chylomicron remnant particles by the liver. St erols selected as cholesterol congeners with functional group variatio ns were incorporated into the emulsions in place of cholesterol and in jected intravenously in rats. Control emulsions contained either no ch olesterol or approximately 1% (by weight) cholesterol. The effects of the different sterol structures on lipolysis and hepatic remnant uptak e were compared with controls to determine the significance of various functional groups. Clearance of emulsion CO was impaired when cholest erol was absent or replaced by cholesteryl chloride, cholesteryl forma te, or 3-keto-cholesterol. Clearance of emulsions containing epicholes terol, where the OH group at the 3-position is in the alpha configurat ion, was similar to control emulsions containing cholesterol. Congener s with an additional hydroxyl group, viz. 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, or 25-hydroxycholesterol, reduced CO cleara nce. Androstenol, which lacks the side chain at the C17-position, also retarded CO clearance from plasma. In contrast, emulsions incorporati ng congeners with side chain variations such as campesterol, beta sito sterol, stigmasterol, or saturated congeners of cholesterol such as ch olestanol, coprostanol and its epimer, epicoprostanol, all were cleare d similarly to emulsions containing cholesterol. In conclusion, for ph ysiological clearance of a chylomicron-like emulsion, the presence of a hydroxyl (-OH) group at the 3-position and an alkyl side chain at th e C17-position of cholesterol are essential, while the structure of th e side chain and the saturation of the ring structure are not critical . The mechanism of the specificity of sterols on the metabolism of pro tein-free emulsions is unclear, but does not relate to changes in micr ofluidity of the surface lipids, nor to the amount or isoform of assoc iated apolipoproteins.